EP1420029B1 - Procédé de synthèse du perindopril et ses sels pharmaceutiquement acceptables - Google Patents

Procédé de synthèse du perindopril et ses sels pharmaceutiquement acceptables Download PDF

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Publication number
EP1420029B1
EP1420029B1 EP03293084A EP03293084A EP1420029B1 EP 1420029 B1 EP1420029 B1 EP 1420029B1 EP 03293084 A EP03293084 A EP 03293084A EP 03293084 A EP03293084 A EP 03293084A EP 1420029 B1 EP1420029 B1 EP 1420029B1
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EP
European Patent Office
Prior art keywords
formula
perindopril
process according
pharmaceutically acceptable
iib
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP03293084A
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German (de)
English (en)
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EP1420029A3 (fr
EP1420029B9 (fr
EP1420029A2 (fr
Inventor
Thierry Dubuffet
Jean-Pierre Lecouve
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Laboratoires Servier SAS
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Laboratoires Servier SAS
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Filing date
Publication date
Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Priority to ES03293084T priority Critical patent/ES2300555T3/es
Priority to AT03293084T priority patent/ATE386745T1/de
Priority to DE60319196T priority patent/DE60319196T2/de
Priority to SI200331193T priority patent/SI1420029T1/sl
Priority to EP03293084A priority patent/EP1420029B9/fr
Priority to DK03293084T priority patent/DK1420029T3/da
Priority to PT03293084T priority patent/PT1420029E/pt
Publication of EP1420029A2 publication Critical patent/EP1420029A2/fr
Publication of EP1420029A3 publication Critical patent/EP1420029A3/fr
Priority to UAA200607608A priority patent/UA84898C2/uk
Priority to CA2548405A priority patent/CA2548405C/fr
Priority to NZ547550A priority patent/NZ547550A/en
Priority to KR1020067013586A priority patent/KR100825537B1/ko
Priority to CNB2004800363546A priority patent/CN100453552C/zh
Priority to JP2006543583A priority patent/JP4377413B2/ja
Priority to MYPI20045097A priority patent/MY139289A/en
Priority to GEAP20049501A priority patent/GEP20084370B/en
Priority to AU2004312185A priority patent/AU2004312185B2/en
Priority to BRPI0417423A priority patent/BRPI0417423B1/pt
Priority to US10/582,283 priority patent/US7279583B2/en
Priority to PCT/FR2004/003166 priority patent/WO2005066198A1/fr
Priority to ZA200604369A priority patent/ZA200604369B/en
Priority to PL380410A priority patent/PL211485B1/pl
Priority to EA200601086A priority patent/EA012034B1/ru
Priority to ARP040104613A priority patent/AR047327A1/es
Priority to MA29083A priority patent/MA28222A1/fr
Priority to NO20063012A priority patent/NO20063012L/no
Priority to HK07102976.7A priority patent/HK1095839A1/xx
Application granted granted Critical
Publication of EP1420029B1 publication Critical patent/EP1420029B1/fr
Priority to CY20081100813T priority patent/CY1108238T1/el
Publication of EP1420029B9 publication Critical patent/EP1420029B9/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof

Definitions

  • the present invention relates to a method for synthesizing perindopril of formula (I): and pharmaceutically acceptable salts thereof.
  • Perindopril as well as its pharmaceutically acceptable salts, and more particularly its tert-butylamine salt, possess valuable pharmacological properties.
  • Their main property is to inhibit angiotensin I converting enzyme (or kininase II), which allows on the one hand to prevent the transformation of decapeptide angiotensin I into octapeptide angiotensin II (vasoconstrictor), and to on the other hand to prevent the degradation of the bradykinin (vasodilator) into inactive peptide. Both of these actions contribute to the beneficial effects of perindopril in cardiovascular diseases, especially high blood pressure and heart failure.
  • the patent EP 0 308 341 describes the industrial synthesis of perindopril by coupling the benzyl ester of (2 S , 3a S , 7a S ) -octahydroindole 2-carboxylic acid with ethyl ester of N - [( S ) -1-carboxybutyl] - ( S ) -alanine in the presence of dicyclohexylcarbodiimide, followed deprotection of the carboxylic group of the heterocycle by catalytic hydrogenation.
  • This process has drawbacks related to the use of dicyclohexylcarbodiimide.
  • the Applicant has developed a process for synthesizing perindopril which uses other coupling agents.
  • the catalytic hydrogenation is preferably carried out under a hydrogen pressure of less than 10 bar.
  • the catalytic hydrogenation is preferably carried out under a hydrogen pressure of between 10 and 35 bar.
  • the lyophilizate obtained in the preceding stage (200 g) is dissolved in 2.8 l of ethyl acetate, then 44 g of tert-butylamine and 400 ml of ethyl acetate are added. The suspension obtained is then brought to reflux until complete dissolution, then the solution obtained is filtered hot and cooled with stirring to a temperature of 15-20 ° C. The precipitate obtained is then filtered, resuspended with ethyl acetate, dried and then ground to yield the expected product with a yield of 95%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

  • La présente invention concerne un procédé de synthèse du perindopril de formule (I) :
    Figure imgb0001
     et de ses sels pharmaceutiquement acceptables.
  • Le perindopril, ainsi que ses sels pharmaceutiquement acceptables, et plus particulièrement son sel de tert-butylamine, possèdent des propriétés pharmacologiques intéressantes.
    Leur principale propriété est d'inhiber l'enzyme de conversion de l'angiotensine I (ou kininase II), ce qui permet d'une part d'empêcher la transformation du décapeptide angiotensine I en octapeptide angiotensine II (vasoconstricteur), et d'autre part de prévenir la dégradation de la bradykinine (vasodilatateur) en peptide inactif.
    Ces deux actions contribuent aux effets bénéfiques du perindopril dans les maladies cardiovasculaires, tout particulièrement l'hypertension artérielle et l'insuffisance cardiaque.
  • Le perindopril, sa préparation et son utilisation en thérapeutique ont été décrits dans le brevet européen EP 0 049 658 .
  • Compte-tenu de l'intérêt pharmaceutique de ce composé, il était important de pouvoir y accéder avec un procédé de synthèse performant, facilement transposable à l'échelle industrielle, conduisant au perindopril avec un bon rendement, et surtout avec une excellente pureté.
    Le brevet EP 0 308 341 décrit la synthèse industrielle du perindopril par couplage de l'ester benzylique de l'acide (2S, 3aS, 7aS)-octahydroindole 2-carboxylique avec l'ester éthylique de la N-[(S)-1-carboxybutyl]-(S)-alanine en présence de dicyclohexylcarbodiimide, suivie de la déprotection du groupement carboxylique de l'hétérocycle par hydrogénation catalytique.
    Ce procédé présente des inconvénients liés à l'utilisation du dicyclohexylcarbodiimide.
  • La Demanderesse a mis au point un procédé de synthèse du perindopril qui utilise d'autres agents de couplage.
  • Plus spécifiquement, la présente invention concerne un procédé de synthèse du perindopril caractérisé en ce que l'on met en réaction l'ester benzylique de formule (IIa) ou (IIb) :
    Figure imgb0002
     ou le sel d'addition de l'ester de formule (IIa) ou (IIb) avec un acide minéral ou organique,
    avec le composé de formule (III):
    Figure imgb0003
     en présence d'un agent de couplage choisi parmi les réactifs et couples de réactifs suivants :
    • 1-(3-diméthylaminopropyl)-3-éthyl-carbodiimide chlorhydrate /1-hydroxybenzotriazole, et anhydride propanephosphonique,
    en présence éventuelle d'une base,
    pour conduire après hydrogénation catalytique en présence de palladium au perindopril de formule (I), que l'on transforme, si on le souhaite, en un sel pharmaceutiquement acceptable tel que le sel de tert-butylamine.
  • Lorsqu'on part du composé de formule (IIa), l'hydrogénation catalytique est préférentiellement effectuée sous une pression d'hydrogène inférieure à 10 bars.
  • Lorsqu'on part du composé de formule (IIb), l'hydrogénation catalytique est préférentiellement effectuée sous une pression d'hydrogène comprise entre 10 et 35 bars.
  • L'exemple ci-dessous illustre l'invention.
    • Référence Exemple 1 : (2S, 3aS, 7aS)-1-{(1S)-1-1(1S)-[-(Ethoxycarbonyl)-butylamino]-propionyl}-octahydro-1H-indole-2-carboxylate de benzyle :
  • Dans un réacteur sous agitation sont introduits 200 g du paratoluènesulfonate de l'ester benzylique de l'acide (2S, 3aS, 7aS)-octahydroindole 2-carboxylique, 65 ml de triéthylamine, 1 l d'acétate d'éthyle puis, après 10 mn d'agitation à température ambiante, 100 g de N-[(S)-carbéthoxy-1-butyl]-(S)-alanine, et 175 g de O-(benzotriazol-1-yl)-1,1,3,3-bis(tétraméthylène)-uronium hexafluorophosphate. Le mélange hétérogène est ensuite porté à 30°C pendant 3h sous bonne agitation, puis il est refroidi à 0°C et filtré.
    Le filtrat est ensuite lavé, puis évaporé à sec pour conduire au produit attendu.
    • Exemple 2 : Acide (2S, 3aS, 7aS)-1-{(2S)-1-[(1S)-1-(éthoxycarbonyl)-butylamino]-propionyl}-octahydro-1H-indok-2-carboxylique :
  • Le résidu obtenu dans le stade précédent (200 g) est mis en solution dans 200 ml de méthylcyclohexane et transféré dans un hydrogénateur, puis 26 g de charbon palladié à 5% en suspension dans 80 ml de méthylcyclohexane sont ajoutés, suivis de 640 ml d'eau.
    Le mélange est ensuite hydrogéné sous une pression de 0,5 bar, à une température comprise entre 15 et 30°C, jusqu'à absorption de la quantité théorique d'hydrogène.
    Après filtration du catalyseur, la phase aqueuse du filtrat est lavée par du méthylcyclohexane, puis lyophilisée pour conduire au produit attendu avec un rendement de 94%.
    • Exemple 3 : Sel de tert-butylamine de l'acide (2S, 3aS, 7aS)-1-{(2S)-2-[(1S)-1-(étlroxycarbonyl)-butylamino]-propionyl}-octahydro-1H-indole 2-carboxylique :
  • Le lyophilisat obtenu dans le stade précédent (200 g) est mis en solution dans 2,8 l d'acétate d'éthyle, puis 44 g de tert-butylamine et 400 ml d'acétate d'éthyle sont ajoutés.
    La suspension obtenue est ensuite portée au reflux jusqu'à dissolution totale, puis la solution obtenue est filtrée à chaud et refroidie sous agitation jusqu'à une température de 15-20°C.
    Le précipité obtenu est alors filtré, réempâté à l'acétate d'éthyle, séché puis broyé pour conduire au produit attendu avec un rendement de 95%.

Claims (6)

  1. Procédé de synthèse industrielle du perindopril de formule (I)
    Figure imgb0004
     et de ses sels pharmaceutiquement acceptables, caractérisé en ce que l'on met en réaction l'ester benzylique de formule (IIa) ou (IIb) :
    Figure imgb0005
     ou le sel d'addition de l'ester de formule (IIa) ou (IIb) avec un acide minéral ou organique,
    avec le composé de formule (III) :
    Figure imgb0006
     en présence d'un agent de couplage choisi parmi les réactifs et couples de réactifs suivants :
    1-(3-diméthylaminopropyl)-3-éthyl-carbodiimide chlorhydrate / 1-hydroxybenzotriamle, et anhydride propanephosphonique,
    en présence éventuelle de base,
    pour conduire après hydrogénation catalytique en présence de palladium au perindopril de formule (I), que l'on transforme, si on le souhaite, en un sel pharmaceutiquement acceptable.
  2. Procédé de synthèse selon la revendication 1 du perindopril sous sa forme de sel de tert-butylamine.
  3. Procédé selon la revendication 1, caractérisé en ce que l'on part du composé de formule (IIa).
  4. Procédé selon la revendication 1, caractérisé en ce que l'on part du composé de formule (IIb).
  5. Procédé selon la revendication 3, caractérisé en ce que la réaction d'hydrogénation est effectuée sous une pression d'hydrogène inférieure à 10 bars.
  6. Procédé selon la revendication 4, caractérisé en ce que la réaction d'hydrogénation est effectuée sous une pression d'hydrogène comprise entre 10 et 35 bars.
EP03293084A 2003-12-10 2003-12-10 Procédé de synthèse du perindopril et ses sels pharmaceutiquement acceptables Expired - Lifetime EP1420029B9 (fr)

Priority Applications (27)

Application Number Priority Date Filing Date Title
ES03293084T ES2300555T3 (es) 2003-12-10 2003-12-10 Procedimiento de sintesis de perindopril y de sus sales farmaceuticamente aceptables.
AT03293084T ATE386745T1 (de) 2003-12-10 2003-12-10 Verfahren für die synthese von perindopril und seiner pharmazeutisch annehmbaren salzen
DE60319196T DE60319196T2 (de) 2003-12-10 2003-12-10 Verfahren für die Synthese von Perindopril und seiner pharmazeutisch annehmbaren Salzen
SI200331193T SI1420029T1 (sl) 2003-12-10 2003-12-10 Postopek za sintezo perindoprila in njegovih farmacevtsko sprejemljivih soli
EP03293084A EP1420029B9 (fr) 2003-12-10 2003-12-10 Procédé de synthèse du perindopril et ses sels pharmaceutiquement acceptables
DK03293084T DK1420029T3 (da) 2003-12-10 2003-12-10 Fremgangsmåde til syntese af perindopril og farmaceutisk acceptable salte heraf
PT03293084T PT1420029E (pt) 2003-12-10 2003-12-10 Processo de síntese do perindopril e dos seus sais farmaceuticamente aceitáveis
UAA200607608A UA84898C2 (uk) 2003-12-10 2004-09-12 Спосіб синтезу периндоприлу і його фармацевтично прийнятних солей
EA200601086A EA012034B1 (ru) 2003-12-10 2004-12-09 Новый способ синтеза периндоприла и его фармацевтически приемлемых солей
MYPI20045097A MY139289A (en) 2003-12-10 2004-12-09 Process for the synthesis of perindopril and pharmaceutically acceptable salts thereof
ZA200604369A ZA200604369B (en) 2003-12-10 2004-12-09 Method for the synthesis of perindopril and the pharmaceutically-acceptable salts thereof
KR1020067013586A KR100825537B1 (ko) 2003-12-10 2004-12-09 페린도프릴 및 이의 약학적으로 허용되는 염의 합성 방법
CNB2004800363546A CN100453552C (zh) 2003-12-10 2004-12-09 合成培哚普利及其可药用盐的方法
JP2006543583A JP4377413B2 (ja) 2003-12-10 2004-12-09 ペリンドプリルおよび薬学的に許容され得るその塩を合成する方法
CA2548405A CA2548405C (fr) 2003-12-10 2004-12-09 Nouveau procede de synthese du perindropil et de ses sels pharmaceutiquement acceptables
GEAP20049501A GEP20084370B (en) 2003-12-10 2004-12-09 Synthesis of perindopril and the pharmaceutically-acceptable salts thereof
AU2004312185A AU2004312185B2 (en) 2003-12-10 2004-12-09 Method for the synthesis of perindopril and the pharmaceutically-acceptable salts thereof
BRPI0417423A BRPI0417423B1 (pt) 2003-12-10 2004-12-09 processo de síntese do perindopril e de seus sais farmaceuticamente aceitáveis
US10/582,283 US7279583B2 (en) 2003-12-10 2004-12-09 Process for the synthesis of perindopril and pharmaceutically acceptable salts thereof
PCT/FR2004/003166 WO2005066198A1 (fr) 2003-12-10 2004-12-09 Nouveau procede de synthese du perindopril et de ses sels pharmaceutiquement acceptables
NZ547550A NZ547550A (en) 2003-12-10 2004-12-09 New process for the synthesis of perindopril and pharmaceutically acceptable salts thereof
PL380410A PL211485B1 (pl) 2003-12-10 2004-12-09 Sposób syntezy perindoprilu i jego farmaceutycznie dopuszczalnych soli
ARP040104613A AR047327A1 (es) 2003-12-10 2004-12-10 Procedimiento para la sintesis de perindopril y de sus sales farmaceuticamente aceptables
MA29083A MA28222A1 (fr) 2003-12-10 2006-06-07 Nouveau procede de synthese du perindopril et de ses sels pharmaceutiquement acceptables
NO20063012A NO20063012L (no) 2003-12-10 2006-06-28 Fremgangsmaten for syntesen av perindopril og farmasoytisk akseptable salter derav
HK07102976.7A HK1095839A1 (en) 2003-12-10 2007-03-20 Method for the synthesis of perindopril and the pharmaceutically-acceptable salts thereof
CY20081100813T CY1108238T1 (el) 2003-12-10 2008-05-16 Μεθοδος συνθεσης της περινδοπριλης και των φαρμακευτικως αποδεκτων αλατων της

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP03293084A EP1420029B9 (fr) 2003-12-10 2003-12-10 Procédé de synthèse du perindopril et ses sels pharmaceutiquement acceptables

Publications (4)

Publication Number Publication Date
EP1420029A2 EP1420029A2 (fr) 2004-05-19
EP1420029A3 EP1420029A3 (fr) 2004-05-26
EP1420029B1 true EP1420029B1 (fr) 2008-02-20
EP1420029B9 EP1420029B9 (fr) 2008-11-12

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EP03293084A Expired - Lifetime EP1420029B9 (fr) 2003-12-10 2003-12-10 Procédé de synthèse du perindopril et ses sels pharmaceutiquement acceptables

Country Status (27)

Country Link
US (1) US7279583B2 (fr)
EP (1) EP1420029B9 (fr)
JP (1) JP4377413B2 (fr)
KR (1) KR100825537B1 (fr)
CN (1) CN100453552C (fr)
AR (1) AR047327A1 (fr)
AT (1) ATE386745T1 (fr)
AU (1) AU2004312185B2 (fr)
BR (1) BRPI0417423B1 (fr)
CA (1) CA2548405C (fr)
CY (1) CY1108238T1 (fr)
DE (1) DE60319196T2 (fr)
DK (1) DK1420029T3 (fr)
EA (1) EA012034B1 (fr)
ES (1) ES2300555T3 (fr)
GE (1) GEP20084370B (fr)
HK (1) HK1095839A1 (fr)
MA (1) MA28222A1 (fr)
MY (1) MY139289A (fr)
NO (1) NO20063012L (fr)
NZ (1) NZ547550A (fr)
PL (1) PL211485B1 (fr)
PT (1) PT1420029E (fr)
SI (1) SI1420029T1 (fr)
UA (1) UA84898C2 (fr)
WO (1) WO2005066198A1 (fr)
ZA (1) ZA200604369B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2413128A (en) * 2004-04-13 2005-10-19 Neopharma Ltd Process for the preparation of perindopril
PT1679072E (pt) * 2005-01-06 2008-12-22 Ipca Lab Ltd Processo para a síntese de derivados de ácido (2s,3as,7as)-1-(s)-alanil-octa-hidro-1h-indole-2-carboxílico e utilização na síntese de perindopril
WO2006131828A1 (fr) * 2005-06-08 2006-12-14 Aurobindo Pharma Limited Un procede de preparation de perindopril
EP2318365B1 (fr) 2008-06-24 2015-08-12 Mylan Laboratories Limited Nouvelles formes polymorphes de perindopril (l)-arginine et processus de préparation correspondants
WO2016178591A2 (fr) 2015-05-05 2016-11-10 Gene Predit, Sa Marqueurs génétiques et traitement de l'obésité masculine
FR3050380B1 (fr) 2016-04-20 2020-07-10 Les Laboratoires Servier Composition pharmaceutique comprenant un betabloquant, un inhibiteur de l'enzyme de conversion et un antihypertenseur ou un ains.

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2807431B1 (fr) * 2000-04-06 2002-07-19 Adir Nouveau procede de synthese du perindopril et de ses sels pharmaceutiquement acceptables

Also Published As

Publication number Publication date
AU2004312185B2 (en) 2010-09-30
DK1420029T3 (da) 2008-06-16
CA2548405A1 (fr) 2005-07-21
CN1890258A (zh) 2007-01-03
US7279583B2 (en) 2007-10-09
EA012034B1 (ru) 2009-06-30
EP1420029A3 (fr) 2004-05-26
PL211485B1 (pl) 2012-05-31
KR20060097060A (ko) 2006-09-13
DE60319196D1 (de) 2008-04-03
JP2008505845A (ja) 2008-02-28
JP4377413B2 (ja) 2009-12-02
AR047327A1 (es) 2006-01-18
AU2004312185A1 (en) 2005-07-21
EP1420029B9 (fr) 2008-11-12
EP1420029A2 (fr) 2004-05-19
ES2300555T3 (es) 2008-06-16
ZA200604369B (en) 2007-11-28
PL380410A1 (pl) 2007-01-22
GEP20084370B (en) 2008-05-13
SI1420029T1 (sl) 2008-08-31
HK1095839A1 (en) 2007-05-18
NZ547550A (en) 2009-11-27
EA200601086A1 (ru) 2006-12-29
BRPI0417423B1 (pt) 2017-03-28
DE60319196T2 (de) 2009-04-30
US20070093663A1 (en) 2007-04-26
UA84898C2 (uk) 2008-12-10
CA2548405C (fr) 2010-07-27
NO20063012L (no) 2006-06-28
CY1108238T1 (el) 2014-02-12
ATE386745T1 (de) 2008-03-15
MY139289A (en) 2009-09-30
CN100453552C (zh) 2009-01-21
WO2005066198A1 (fr) 2005-07-21
MA28222A1 (fr) 2006-10-02
BRPI0417423A (pt) 2007-03-06
PT1420029E (pt) 2008-04-14
KR100825537B1 (ko) 2008-04-25

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